We have shown that immunization with live, replication-competent Ad-HIV or Ad-SIV envelope recombinant vaccines not only elicits cellular immunity, but also primes strong antibody responses that develop following administration of booster immunizations with envelope protein. These antibodies display a variety of functional activities. The most desirable for an HIV/AIDS vaccine is neutralizing activity that is able to prevent infection following exposure to the virus. We have shown in pre-clinical studies that our prime/boost vaccine approach results in neutralizing antibodies that can confer apparent sterilizing immunity following challenge of rhesus macaques with an HIV/SIV chimeric SHIV virus. HIV/SIV infection is initially manifested as small foci of infected cells. Within 2 to 6 days, virus spreads from these foci to draining lymph nodes, subsequently leading to systemic infection. In addition to neutralization, our vaccine approach elicits antibodies that possess other functional activities that although not able to block infection, may contribute to control of the initial viral burden by limiting the spread of virus from these foci of infection. Such activities include antibody dependent cellular cytotoxicity (ADCC), and antibody dependent cell-mediated viral inhibition (ADCVI). Our recent studies, again in the rhesus macaque model, demonstrate that these non-neutralizing antibody activities are correlated with lower viral burdens. Since HIV is transmitted mainly at rectal/genital mucosal sites, a key goal of HIV vaccine development is to elicit mucosal immunity. The Ad-recombinant prime/protein boost strategy induces antibodies in mucosal secretions which we have shown can inhibit transcytosis of SIV across an epithelial cell barrier, suggesting another mechanism which may contribute to protection. In comprehensive studies aimed at fully characterizing vaccine-elicited antibodies, their avidity is being investigated in order to determine whether this characteristic plays a role in protective efficacy. Importantly, the ability of the vaccine approach to elicit long lasting memory B cells, a critical property of vaccines that provide essentially life-long protection, is being explored. Overall, our recent studies demonstrate that the replication-competent Ad-recombinant prime/envelope protein boost approach induces long-lasting, high-titered antibodies with a spectrum of activities both in serum and mucosal secretions, which together contribute to strong protection against viral challenge in non-human primate models.